Current Insights on Dyslipidaemia Management for Prevention of Atherosclerotic Cardiovascular Disease: A Malaysian Perspective

Dyslipidaemia is highly prevalent in the Malaysian population and is one of the main risk factors for atherosclerotic cardiovascular disease (ASCVD). Low-density lipoprotein cholesterol (LDL-C) is recognised as the primary target of lipid-lowering therapy to reduce the disease burden of ASCVD. Framingham General CV Risk Score has been validated in the Malaysian population for CV risk assessment. The Clinical Practice Guidelines (CPG) on the management of dyslipidaemia were last updated in 2017. Since its publication, several newer randomised clinical trials have been conducted with their results published in research articles and compared in meta-analysis. This underscores a need to update the previous guidelines to ensure good quality care and treatment for the patients. This review summarises the benefits of achieving LDL-C levels lower than the currently recommended target of < 1.8mmol/L without any safety concerns. In most high and very high-risk individuals, statins are the first line of therapy for dyslipidaemia management. However, certain high-risk individuals are not able to achieve the LDL-C goal as recommended in the guideline even with high-intensity statin therapy. In such individuals, lower LDL-C levels can be achieved by combining the statins with non-statin agents such as ezetimibe and PCSK9 inhibitors. Emerging non-statin lipid-lowering therapies and challenges in dyslipidaemia management are discussed in this article. The review also summarises the recent updates on local and international guidelines for dyslipidaemia management.


Introduction
Cardiovascular diseases (CVDs) are the most common cause of mortality around the world (1-3). Major cardiovascular risk factors include dyslipidaemia, hypertension, smoking, diabetes, obesity, and physical inactivity. The global prevalence of elevated total cholesterol was estimated to be 11.9% (4). Elevated levels of total cholesterol, triglyceride, low-density lipoprotein cholesterol (LDL-C) and low levels of high-density lipoprotein cholesterol were highly prevalent in the Malaysian population (5). Current data on the safety of very low LDL-C supports the hypothesis that 'lower is better' (6).
In Malaysia, CVDs have been reported as the leading cause of death among noncommunicable diseases (NCD) (7, 8). The results of the National Health and Morbidity Survey (NHMS) published in 2019 found one in four people mostly in the age group of 40 years old-59 years old to be unaware of their hypercholesterolemia status (9). The Malaysian National Cardiovascular Disease Database (NCVD) registry showed 54.8% of patients with percutaneous coronary intervention (PCI) and 38.6% of patients with the acute coronary syndrome (ACS) had hypercholesterolemia (10,11).
Elevated LDL-C levels in the blood are responsible for accumulation and retention of LDL particles in the endothelial wall leading to accelerated atherosclerotic plaque progression and rupture. The thrombus associated with plaque rupture obstructs the coronary blood vessel leading to adverse cardiovascular (CV) events (12). For this reason, plasma LDL-C levels have been linked to the development of atherosclerotic cardiovascular disease (ASCVD) (13,14). Several clinical trials have shown that lowering LDL-C level reduces CV events (15)(16)(17). Being a positive risk factor for ASCVD, most guidelines identify LDL-C as a target of treatment in dyslipidaemia and CVD patients moderate and low CV risk. Similar LDL-C goals were recommended by the 2017 CPG on Primary and Secondary Prevention of CVD (20,26).

Overview of Dyslipidaemia Management Algorithm
Treatment algorithms help clinicians to select the appropriate treatment modalities for attaining LDL-C goals (Figure 1). Most very high-risk patients fail to achieve LDL-C goals with monotherapy. Hence, combination therapy is recommended for these patients. They are treated with a maximum tolerable dose of statin in combination with ezetimibe or PCSK9 inhibitors as required to lower the LDL-C levels to target (24).

Benefits of Lowering LDL-C
Mounting evidence from published literature advocates that lowering LDL-C level leads to overall CV benefits. Aggressive lowering of LDL-C in extreme risk and very high-risk patients results in further reduction in CV events (27,28).
The landmark clinical trials with lipidlowering agents that substantiated the benefits of lowering LDL-C levels include Further CV Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER), ODYSSEY OUTCOMES and Open Label Study of Long-Term Evaluation against LDL-C (OSLER) (29)(30)(31). The FOURIER trial was a randomised, double-blind trial including ASCVD patients (N = 27,564) with high LDL-C levels (> 1.8 mmol/L) and receiving statin therapy. The randomised patients were given evolocumab [a monoclonal antibody that blocks proprotein convertase subtilisin-kexin type 9 (PCSK9)] or a placebo. The median baseline LDL-C was 2.4 mmol/L. The least-squares mean percentage reduction in LDL-C levels at week 48 with evolocumab was 59% compared to placebo (P < 0.001). Lowering of LDL-C levels to a median of 0.78 mmol/L further reduced the risk of CV events. The risk of the primary composite endpoint of CV death, myocardial infarction (MI), stroke, hospitalisation for unstable angina or coronary revascularisation was significantly reduced by evolocumab (P < 0.001). Similarly, there was a significant reduction in the risk of the secondary composite endpoint of CV death, myocardial infarction or stroke by evolocumab (P < 0.001) (29). The randomised, double-blind, multicentre ODYSSEY OUTCOMES trial was populations. Preferably, the adopted CV risk model should be remodeled based on data pertaining to the local population to define the risk categories (20). The Framingham Risk Score-Cardiovascular Disease (FRS-CVD) for 10-year CV risk calculation for CVD risk stratification has been found to be more accurate than the Framingham Risk Score-Coronary heart disease (FRS-CHD), QRESEARCH cardiovascular risk algorithm score (QRISK2), Joint British Society risk calculator 3 (JBS3), ACC/AHA atherosclerotic cardiovascular disease (ASCVD) risk score and WHO/ISH risk charts (21). The FRS-General CVD risk score tool has been developed from a treatment-naive population or those subjected to minimum treatment. In addition, FRS-CVD is a straightforward and simple to use tool (20). The FRS and Systematic Coronary Risk Evaluation (SCORE) were found to be efficient in identifying patients at high risk for CVD in a local study from Malaysia (22). The FRS-General CVD risk score tool has good calibration and discriminates moderately well for the Malaysian population (23). Hence FRS-General CVD risk score tool is highly recommended for assessing CV risk in the Malaysian population (20).

Cardiovascular Risk Stratification
Based on CV risk stratification, patients are categorised into low risk, moderate risk, high risk and very high-risk groups by the 2017 Malaysian CPG on the Management of Dyslipidaemia and the 2019 ESC/EAS Guideline on the Management of Dyslipidaemias (20,24). Meanwhile, the 2018 ACC/AHA Guideline on the Management of Blood Cholesterol focuses on cholesterol management in very high-risk ASCVD patients (25) (Table 1).

Malaysian Guidelines on Dyslipidaemia Management
Presently two major CPGs are available in Malaysia-CPG on the Management of Dyslipidaemia (20) and CPG on Primary and Secondary Prevention of CVD (26). According to the 2017 Malaysian CPG on the Management of Dyslipidaemia, target LDL-C levels are based on the patient's risk profile for CVD. For patients with very high CV risk, the target LDL-C should be < 1.8 mmol/L or > 50% reduction from baseline. For high CV risk patients, LDL-C of ≤ 2.6 mmol/L or > 50% reduction from baseline is recommended. Target LDL-C of < 3.0 mmol/L is recommended for patients with intermediate/  The primary composite outcome of death, myocardial infarction, unstable angina, coronary revascularisation, stroke, transient ischaemic attack and chronic heart failure hospitalisation at 1 year was significantly lower in the evolocumab group as compared to the standard of care group (0.95% versus 2.18%; P = 0.003) (31). Several recent randomised clinical trials have reported very low achieved LDL-C levels in patients with dyslipidaemia (Table 2). A meta-analysis revealed 19% relative risk reduction for major vascular events with a 1 mmol/L reduction in LDL-C levels. This risk reduction was independent of baseline LDL-C levels (32). Similar results were seen in a metaanalysis of 11 randomised clinical trials on patients (N = 130,070) treated with intensive conducted on patients (N = 18,924) with ACS who had a mean baseline LDL-C level of 2.38 ± 0.80 mmol/L and were receiving high dose statin therapy. In intention-to-treat analysis, the mean LDL-C in the alirocumab group was 1.0 mmol/L and 1.7 mmol/L at 4 months and 48 months, respectively. Alirocumab significantly reduced the risk of a composite end-point event (P < 0.001). Those treated with alirocumab had a lower risk of major adverse CV events (30).
The OSLER-1 trial on lipid effects and exposure-dependent safety of evolocumab with a follow-up of 5 years (N = 1,324) found a decrease in the baseline LDL-C from 3.6 mmol/L to 1.6 mmol/L. About 30% (n = 393) and about 7% (n = 91) patients achieved LDL-C levels of < 1.0 mmol/L and < 0.6 mmol/L, respectively.  cumulative exposure to LDL-C can prevent/ minimise the risk of ASCVD events (35). Another study has proved that the risk of having CVD events in future is associated with cumulative exposure to LDL-C. This was calculated from the area under the LDL-C versus age curve and the risk was determined by the time course of area accumulation (3). A consistent dose-dependent link between the absolute amount of LDL-C exposure and the risk of ASCVD was observed by Ference et al. (14) emphasising the importance of treating dyslipidaemia early, which may lead to the need for less severe treatment in the long run.

Safety Profile in Lower LDL-C Scenario
There have been concerns about possible side effects of very low LDL-C levels. These concerns were addressed in the breakthrough clinical trials that evaluated the efficacy and safety outcomes of lowered LDL-C levels by lipid-lowering agents. In the FOURIER trial, there was no significant difference in adverse events between the evolocumab and placebo groups (29). In the ODYSSEY OUTCOMES trial, the occurrence of the adverse events was similar in the alirocumab group and placebo (30). In the OSLER-1 trial, there was no difference in the rate of adverse events (AEs) reported in these patients compared to those with LDL-C ≥ 1.0 mmol/L. Neutralising antibodies were not detected and evolocumab was found to be safe and well-tolerated (31). and less intensive lipid-lowering therapy. The patients were administered statins, ezetimibe or PCSK9 inhibitor and were followed up for 2 years. The group with lower LDL-C (< 1.8 mmol/L) achieved a median LDL-C level of 1.6 mmol/L; whereas the achieved LDL-C level in the group with higher LDL-C were reduced further in the lower LDL-C group (< 1.8 mmol/L) (33). Intensive reduction in LDL-C levels was associated with further reduction in CV events (34).
Maintaining optimal lipid levels from a very early age will reduce the risk of ASCVD. The magnitude and cumulative exposure duration to LDL-C and other lipoproteins are responsible for their deleterious effects. The cumulative LDL-C exposure is estimated by multiplying the age by plasma LDL-C concentration and gives an approximate estimate of the total atherosclerotic plaque burden. Cumulative risk of MI is measured on a log scale. As the LDL-C level maintained throughout life increases and the age at which the cumulative LDL-C exposure threshold exceeds 5,000 mg-years, the risk of ACS happens earlier in life. Once the threshold is exceeded the atherosclerotic plaque burden will increase the risk of MI. Hence, maintaining lower

Rationale for lowering LDL-C for longer duration
i) Lowering of LDL-C level results in significant reduction in atherosclerotic CV events (27,28).
ii) Intensive lowering of LDL-C levels to achieve treatment goals is well-tolerated and safe without severe adverse events (41).
iii) The duration of cumulative LDL-C exposure is associated with future CV events. In young individuals, the risk for ASCVD can be reduced by maintaining ideal lipid levels from an early age so that they can benefit from lifelong exposure to reduced LDL-C levels (3,35).

Challenges in the Current Management of Dyslipidaemia
Lowering LDL-C to even 0.3 mmol/L was associated with an increase in CV benefits without attaining a plateau stage (27). Patients with very high and extreme risk of ASCVD require aggressive treatment modalities to reduce atherogenic lipoprotein cholesterol to prevent major atherosclerotic CV events. Targeting to achieve lower LDL-C levels with moderate and high-intensity statin monotherapy or combination therapy with add-on non-statins is the generally followed treatment regimen (25).
The cost-effectiveness, CV clinical benefits and co-morbid conditions need to be considered before achieving very low LDL-C levels (27). The safety and tolerability of PCSK9 inhibitors along with LDL-C lowering to exceptional levels and related CV benefits make them the preferred treatment option for dyslipidaemia (42). However, high cost is responsible for the limited use of PSCK9 inhibitors (43).
There are many plausible reasons for not achieving LDL-C goals. Lack of adherence to medication is a contributing factor. Poor adherence deters the benefits of lipid-lowering therapy and the patient becomes vulnerable to CV events. The lack of affordability of medicines, polypharmacy, forgetfulness, doctorpatient relationship, inability to understand label instructions or the need to take the medication are some of the factors responsible for poor adherence. Simple to follow regimens, clear instructions, family support, promoting self-monitoring, providing appointments or follow-up visit reminders and patient education could help improve adherence and The Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) has shown that individuals who achieved very low LDL-C level (< 0.8 mmol/L) had a similar safety profile as patients with high LDL-C levels. The adjusted hazard ratio (HR) of the primary efficacy composite of major coronary events, or stroke was significantly lower in patients with LDL-C level < 0.8 mmol/L (adjusted HR = 0.79; P = 0.001) compared to those with ≥ 1.8 mmol/L (34).
A meta-analysis performed on two groups (one group was on statin therapy and another group on non-statin therapy) also underscores the safety of reducing LDL-C levels. The data for statin therapy was extracted from cholesterol treatment trialists' collaboration (CTTC). Data obtained from IMPROVE-IT, FOURIER and Randomised Evaluation of the Effects of Anacetrapib through Lipid Modification (REVEAL) trials were considered for non-statin therapy. The overall RR was 0.79 per 1 mmol/L reduction in LDL-C for both statins and nonstatins (P < 0.001). Lowering of baseline LDL-C levels (from 1.6 mmol/L to 0.5 mmol/L) reduced the risk for CV events and was safe with no serious AEs, elevated aminotransferases, newonset diabetes (NOD), haemorrhagic stroke, cancer or myalgias. Therefore, irrespective of the type of lipid-lowering agents, a reduction in 1 mmol/L LDL-C was primarily responsible for better clinical outcomes (36). Another metaanalysis of 27 randomised trials (N = 134,537) revealed that in comparison to control a reduction in 1 mmol/L LDL-C by statin resulted in an absolute reduction in major vascular events (3.27% versus 4.04% per annum) such as stroke (0.67% versus 0.78% per annum), major coronary event (1.45% versus 1.87% per annum) and coronary revascularisation (1.55% versus 1.98% per annum) (37). The lowering of LDL-C as low as 0.78 mmol/L (slope = 0.011; P = 0.779) did not increase the risk for haemorrhagic stroke (38).
Published reports demonstrated that lowering of LDL-C with evolocumab was found to be safe and well-tolerated as the frequency of AE was minimum. There was no effect on glucose metabolism and neutralising antibodies were not detected (39,40). Likewise, another study on alirocumab found no increase in hemorrhagic stroke in patients with ACS and dyslipidaemia, emphasising the safety of lower LDL-C goals (41). These promising data on the safety of very low LDL-C support the hypothesis that 'lower is better'. regulation of LDL-C receptors on the cell surface. This leads to increased LDL-C uptake into cells thereby lowering the serum LDL-C levels and CV risks (50). The US Food and Drug Administration (FDA) has approved two PCSK9 inhibitors, alirocumab and evolocumab. Alirocumab (Praluent) was approved for adult patients with heterozygous familial hypercholesterolemia (HeFH) or established ASCVD requiring additional lowering of LDL-C. Evolocumab (Repatha) is to be used in adult patients with HeFH, homozygous familial hypercholesterolaemia or clinical ASCVD requiring further lowering of LDL-C (51). Unfortunately for HeFH, control rates in Malaysia were lower in comparison to other countries (52).
Apart from PCSK9 inhibitors, small interfering RNA (siRNA) molecule can be used to curtail the hepatic production of PCSK9. Inclisiran is one such long-acting, synthetic siRNA molecule that binds to RNA-induced silencing complex (RISC), thereby inhibiting the translation of PCSK9 messenger RNA (mRNA) (49). Inclisiran injection has been approved recently by US FDA for adults with HeFH or clinical ASCVD along with diet and maximally tolerated statin therapy (53). Moreover, the European Medicines Agency (EMA) had also approved inclisiran in 2020 for adults with primary hypercholesterolaemia or mixed dyslipidaemia along with a low-fat diet. Inclisiran can be used in patients on maximally tolerated statins and those who are not able to take the statins (54). Inclisiran is administered as a subcutaneous injection initially, followed by same dose at 3 months and then once every 6 months (53).
Another LDL-C lowering agent is bempedoic acid which is a prodrug. It inhibits the enzyme adenosine triphosphate-citrate lyase (ACL) in the liver and reduces the availability of precursors for fatty acid and cholesterol synthesis (55). Bempedoic acid (ETC-1002) also activates 5'-adenosine monophosphate-activated protein kinase, thereby effectively reducing serum LDL-C levels (56,57). Bempedoic acid was approved by the US FDA for adults with HeFH or established ASCVD who require additional lowering of LDL-C to achieve treatment goals (55). There is an increasing interest in the use of omega-3 fatty acids supplements. Further research is needed to evaluate the effect of these supplements on reducing LDL-C levels (57).
compliance. Physicians should follow lipid treatment guidelines and reference values in all laboratories need to be standardised based on the recommended Malaysian CPG (20).
Another reason for not achieving LDL-C targets is the adverse effect of statin therapy. The most common are statin-associated muscle symptoms (SAMS) which result in low drug adherence and high drug discontinuation rate. This can be managed with dose adjustment and patient counselling (44). Analysis of the JUPITER trial identified statin therapy as a risk for NOD. Some patients are intolerant to statins and develop skeletal muscle-related symptoms leading to treatment discontinuation. There is an increased risk of development of diabetes associated with statin use; however, the benefits of therapy outweigh the risk for diabetes (45).
The WHO had initiated a global strategy program to strengthen the surveillance of NCD in member countries including Malaysia (46). Presently, a dynamic monitoring system for NCD surveillance is actively present in Malaysia for indicators that are tracked and monitored by the Global Monitoring Framework. The list of 25 indicators includes 'raised total cholesterol' under the monitoring of risk/exposure factors. Even though the NCD surveillance system in Malaysia is quite proficient, there is still a deficiency of necessary data for monitoring the framework's health system metrics. There is a lack of an interconnected electronic medical record (EMR) system between public and private healthcare facilities. Despite the availability of web-based systems, data collection largely depends on manual systems (47).
Enhancing public information and mass communication systems could promote greater awareness among the population. Women in Malaysia seem to have good knowledge and attitude towards CVD risk factors (48). Of note, compared to international data, there is gender bias with respect to care in terms of health care providers not being as attuned to CVD in females compared to males.

Newer therapies on the horizon
Nowadays other than statins, PCSK9 inhibitors, adenosine triphosphate-citrate lyase inhibitors and oligonucleotides are used as lipid-lowering agents. The PCSK9, a serine protease synthesised by liver is responsible for elevated LDL-C levels (49). PCSK9 inhibitors are human monoclonal antibodies directed against PCSK9 enzyme resulting in the up-was a 50% reduction of LDL-C or target LDL-C < 1.4 mmol/L. For statin treated patients (LDL-C 2.5 mmol/L-7.5 mmol/L) or statin naive patients (LDL-C 3.0 mmol/L-7.5 mmol/L), maximally tolerated statin therapy in combination with ezetimibe was recommended to achieve a 50%-80% reduction in LDL-C (target < 1.4 mmol/L). For LDL-C levels > 7.5 mmol/L on admission, LDL-C reduction of > 80% was recommended to attain a target LDL-C of < 1.4 mmol/L. Hence a triple therapy (statin + ezetimibe + PCSK9 inhibitor) might be required to achieve the goal (62).

Recent Advances in Local Guidelines
There has been a recent update of two clinical guidelines in Malaysia wherein the target LDL-C goals for the different risk categories have been revised. The 2020 Malaysian CPG on the management of T2DM recommended a target of LDL-C < 1.4 mmol/L in very high-risk patients (with diabetes and established CVD or target organ damage or ≥ 3 risk factors). However, the recommended LDL-C goals for high-risk patients (with ≥ 10 years of diabetes without target organ damage and no other risk factors) and for moderate-risk patients (< 50 years old with < 10 years of T2DM without additional risk factors) were < 1.8 mmol/L and < 2.6 mmol/L, respectively (63). The target LDL-C recommended by the 2020 Malaysian CPG on the management of T2DM is similar to that recommended by the 2019 ESC/EAS Guideline on the management of dyslipidaemias.
Furthermore, the 2020 Malaysian CPG on the management of ischaemic stroke recommended LDL-C target of < 1.8 mmol/L for high-risk group and in patients with prior ischaemic stroke (secondary prevention of stroke). Lowering of LDL-C to < 3.4mmol/L was recommended for intermediate and low-risk populations (64).

Future Directions in Management of Dyslipidaemia
Non-communicable diseases have become the leading cause of morbidity and mortality. Surveillance by NCD could be improved through implementing electronic records in healthcare facilities in Malaysia. Reducing the burden of NCDs will improve the economic status and ensure healthy living for people worldwide. Ensuring adherence to CPG and addressing the knowledge gaps through training sessions for primary care physicians are recommended

Recent Advances in International Recommendations
The 2018 ACC/AHA Guideline on the Management of Blood Cholesterol recommended a ≥ 50% reduction in LDL-C from baseline (25). Furthermore, the 2019 ESC/EAS Guideline on the Management of Dyslipidaemias recommended more intensive LDL-C reduction. For high-risk patients, ≥ 50% reduction from baseline and < 1.8 mmol/L LDL-C goal was recommended. For very high-risk patients on primary and secondary prevention ≥ 50% reduction from baseline and < 1.4 mmol/L LDL-C level was recommended. In the subset of very high-risk patients, an LDL-C goal of < 1.0 mmol/L was recommended for ASCVD patients on maximally tolerated statin therapy who had second CV events in a duration of 2 years (Table 1) (24). These guidelines recognise all ASCVD patients to be at very high risk for developing adverse CV events in the future. In comparison to 2018 ACC/AHA guidelines, an aggressive LDL-C goal is recommended for these patients (58).
Based on the consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the management of dyslipidaemia and prevention of CVD algorithm, the target LDL-C for extreme risk, very highrisk and high-risk groups were < 1.4 mmol/L, < 1.8 mmol/L and < 2.6 mmol/L, respectively (59). The 2019 ESC Guidelines on diabetes, pre-diabetes and CVD in patients with type 2 diabetes mellitus (T2DM) have recommended LDL-C goal of < 1.4 mmol/L and ≥ 50% LDL-C reduction in T2DM patients with very high CV risk. LDL-C reduction of ≥ 50% and target LDL-C of < 1.8 mmol/L to be advocated for high CV risk patients with T2DM (60).
According to the 2019 ACC/AHA Guideline on the Primary Prevention of CV Disease, ≥ 50% LDL-C reduction was proposed for highrisk patients with ≥ 20% 10-year ASCVD risk. In intermediate-risk patients with a 10-year ASCVD risk of 7.5% to < 20%, the recommended reduction was ≥ 30% (61).
A position paper endorsed by the International Lipid Expert Panel recommended maximally tolerated intensive statin therapy for statin-treated patients with LDL-C < 2.5 mmol/L and high dose statins for statin-naive patients with LDL-C < 3.0 mmol/L. The treatment goal for better management of dyslipidaemia (65). This highlights the need for programmes and workshops to spread awareness about dyslipidaemia and its management amongst the local population in Malaysia (66). Asian countries need to evaluate, accept, and implement the essential recommendations from ESC/EAS and ACC/AHA guidelines for dyslipidaemia management in their respective populations. These countries need to update and tailor their CPG in a way suitable for the target population (67).
Considering the advent of several new clinical data, gaps in the knowledge as well as non-adherence to guidelines make it necessary to update the guidelines regularly to re-evaluate the LDL-C targets as well as consider treatment modalities beyond statins to achieve these new targets. This would facilitate the dissemination of awareness about the management of dyslipidaemia and related risks.